There are three specific aims to this grant proposal. These are to determine the effects of nicotine in tobacco smoking amounts on (1) regional blood flow and (2) regional glucose metabolism in the brains of adult cigarette smokers (3) males and females. Only cigarette smokers will be studied. State-of-the-art imaging technology using positron emission tomography is available and ready to use with equipment already paid for at no extra cost to this grant. Nicotine will be administered by smoking a standardized research cigarette, as well as a nasal spray of a pure solution in order to determine whether the effects observed are due to nicotine alone or nicotine plus other chemicals in tobacco smoke. in addition, blood nicotine and cotinine concentrations will be measured and correlated with the induced functional brain changes. The cerebral blood flow study will compare regional cerebral blood flow following nicotine cigarettes and nicotine spray in 24 (12 male, 12 female) cigarette smokers, in a cross over, repeated measures design. Each subject will undergo two PET sessions scheduled at least one month apart. During each PET session five [15O] water scans will be run. During each of the two PET sessions the first scan (baseline) will be followed by a scan immediately following inhalation of 5% CO2. The third scan will follow either nicotine placebo nasal spray or placebo cigarette administration, the fourth scan will follow either a nicotine cigarette/nasal spray administration, and the fifth scan will follow a repeat nicotine cigarette/nasal spray administration. These functional brain measures will be correlated with arterial and venous blood concentrations of nicotine measured by HPLC. The cerebral metabolic rate study will require that 24 (12 male, 12 female) tobacco smokers undergo two PET scans following injection with [18F]fluorodeoxyglucose, half of the subjects will be randomized to receive nicotine nasal spray and placebo nicotine nasal spray during two separate PET sessions scheduled at least a month apart. The other half will receive nicotine cigarettes and placebo cigarettes. The findings of this research will increase understanding of the effects of nicotine on the brains of normal male and female adults. This new information will make it easier to help understand why tobacco smoking is reinforcing and why it is so difficult to quit. the research proposed is both timely and accomplishable. Such information could lead to novel treatments for nicotine dependence by identifying the involvement of pertinent brain regions as well as possible pathways. This could set the stage for the study of nicotine effects in persons with cofactors for smoking, such as attention deficit disorder or mood disorders.